The formation of diaryl ethers from arenols and aryl groups bearing a leaving group generally requires activated substrates. For aryloxide nucleophiles, the reaction is promoted by copper salts. For instance, Ullman (Ber. 37:853) observed in 1904 that the presence of metallic copper greatly facilitates the substitution of a halogen atom on an aromatic ring with a phenolic oxygen. This method for the synthesis of diaryl ethers, referred to in the contemporary art as the xe2x80x9cUllmann reactionxe2x80x9d or xe2x80x9cUllmann condensationxe2x80x9d, has become widely used in both academic and industrial chemistry. For a review, see Moroz et al. (1974) Russ. Chem. Rev. 43:679.
The Ullmann reaction is typically carried out by heating the reactants at elevated temperatures, e.g., 150-300xc2x0 C., in the presence of a copper salt, which in some cases is present in only a catalytic amount; Ullmann reactions are usually conducted in a solvent, however, in certain cases a solvent is not utilized (the optimal temperature for Ullmann condensations conducted without solvent is typically in range of 180-220xc2x0 C.). To minimize oxidation of the phenolic reactan, the reactions are often performed under an inert atmosphere. See, for example, Weingarten et al. (1964) J. Org. Chem. 29:3624; and Moroz et al. supra.
The Ullmann reaction is widely used in industry, in particular, for the synthesis of various substituted diaryl ethers that are useful as pharmaceuticals, herbicides or insecticides, or as intermediates in the synthesis thereof. A wide variety of diaryl ethers have found use in, for instance, the synthesis of complex natural products. The reaction is also widely used in the general chemical industry. To illustrate, the Ullmann reaction serves as part of a method for the synthesis of phenyl ether (used to prepare heat exchangers and in the perfume industry), substituted phenyl ethers (monomers for thermostable polymers), and polyphenyl ethers, which have found important applications in, for example, oils for creation of ultrahigh vacuums, high-temperature greases, hydraulic liquids, etc.
The conditions used for the copper-mediated coupling of aryl halides and phenols according to the Ullmann reaction are usually harsh, requiring high temperatures and high-boiling, polar solvents (pyridine, collidine, DMF). The classical use of the reaction also has the usual requirement for stoichiometric (or greater) quantities of the copper reagent. The yields of the reaction are substrate dependent and are usually low for transformations involving highly functionalized substrates. For example, during the course of the total synthesis of such antibiotics as vancomycin, attempted Ullmann condensations for the coupling of advanced intermediates were unsuccessful (see, e.g., Williams (1984) Acc Chem. Res. 17:364). Indeed, in the synthesis of pharmaceutical agents, many of the desirable substituents on the substrate aryl moieties may not be sufficiently stable, even when protected, for use in the Ullmann reaction of the prior art. For instance, esters and anhydrides are not stable under the classical Ullmann reaction conditions.
Likewise, the conditions of the classical Ullmann reaction may be too harsh for use in a combinatorial approach to the synthesis of libraries of diaryl ethers and the like, particularly where labile groups are employed, for example, as linker groups or encoding tags (see: Ohlmeyer et al. (1993) PNAS 90:10922; and Brenner et al. (1992) PNAS 89:5381-5383).
Another problem with the classical Ullmann reaction is that many of the solvents that are characteristically relied upon are extremely hazardous. Disposal of reaction by-products, e.g., spent solvent, may accordingly pose significant obstacles, in terms of environmental safety and/or ultimate product cost, to reliance on the classical Ullmann reaction.
Recent efforts to develop Ullmann-type procedures which are applicable to more complex synthetic intermediates have met with only limited success (Evans et al. (1989) J. Am. Chem. Soc. 111:1063; and Boger et al. (1991) J. Org. Chem. 56:4204) or require the presence of an activating group on the substrate bearing the leaving group (for selected examples of activating groups, see Nicolaou et al. (1997) J. Am. Chem. Soc. 119:3421 and Rozanel""skaya et al. (1961) Zhur. Obschc. Khim. 31:758).
One aspect of the present invention relates to novel reaction conditions that allow the efficient synthesis of diaryl ethers from arenes bearing a leaving group and arenols under relatively mild conditions. Another aspect of the present invention relates to the discovery of the dramatic effects of aryl carboxylic acid additives on copper-catalyzed Ullmann-type couplings.
One aspect of the present invention provides a cross-coupling reaction, represented in the general formula: 
wherein
Ar and Arxe2x80x2 independently represent optionally substituted aryl orheteroaryl groups;
YH represents a substituent of Arxe2x80x2 that includes a nucleophilic group, or a group that can be rendered nucleophilic;
X represents a leaving group which can be substituted by the nucleophilic group of Y in a transition metal-catalyzed reaction;
the transition metal catalyst is a complex which catalyzes formation of ArYArxe2x80x2 from ArX and Arxe2x80x2YH;
the metal salt has an anionic portion that is sufficiently basic to neutralize the HX produced in the reaction and/or deprotonate Arxe2x80x2YH and thereby render it a better nucleophile, and the metal salt comprises a soft cation selected from the alkali metal or alkaline earth series, e.g., Rb, Cs, Fr, Sr, Ba or Ra.
In another embodiment of the present invention, the subject method is represented by the transformation above and the attendant definitions, is included in the reaction mixture.
In another embodiment of the present invention, the subject method is represented by the transformation above and the attendant definitions, wherein a stoichiometric amount of a carboxylic acid, e.g., an aryl carboxylic acid, is included in the reaction mixture.
In yet another embodiment of the present invention, the subject method is represented by the transformation above and the attendant definitions, wherein a catalytic amount, e.g., 5 mol %, of a Lewis basic additive, e.g., an ester, and a stoichiometric amount of a carboxylic acid, e.g., an aryl carboxylic acid, are included in the reaction mixture.
In another embodiment of the present invention the transformation depicted above, in any of the aforementioned embodiments, occurs in an aprotic, non-polar solvent, e.g., toluene, at about 110 C.